Safety and Efficacy of Remimazolam in ASA III and IV Patients Undergoing Colonoscopy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Remimazolam in ASA III and IV Patients Undergoing Colonoscopy (NCT02532647), a randomized phase 3 study. The primary outcome is Success Rates of the Procedure.

2. Clinical Question

The question is about a combined procedural outcome, not a single measure of sedation. A participant had to complete the colonoscopy and meet both medication-related conditions to count as a success. This makes the endpoint relevant to whether the procedure could be completed under the assigned study-drug strategy, while also making its interpretation dependent on all parts of the definition.

The study included a placebo comparison and an active-control arm, but the central reported contrast is remimazolam versus placebo. Midazolam results offer another descriptive point of reference, although the registry identifies that arm as open-label. The results do not establish that the groups were otherwise identical in every respect, nor do they answer questions beyond the trial’s recorded population, setting, endpoint, and follow-up period.

3. Trial Design

The registry identifies this as a randomized, parallel-group phase 3 study with an enrollment of 79. It was conducted in patients with ASA III or IV status undergoing colonoscopy. The registry record lists the study as completed, with a start date of 2015-11 and primary completion in 2016-12. The sponsor was Paion UK Ltd.

The study compared remimazolam with placebo under double-blind conditions, and included an additional midazolam arm. The registry summary describes the midazolam arm as open-label. Thus, masking was not described as applying in the same way to every arm. The record does not report further detail about which individuals were masked or how masking was maintained.

All arms included fentanyl pretreatment and allowed fentanyl top-up doses, as described in the arm details. The study-drug regimens differed: remimazolam and midazolam had different initial and top-up doses, while placebo was administered in a double-blind manner. These co-interventions and regimen details are part of the treatment strategies represented by the trial; the primary outcome reflects the overall procedural result under those strategies rather than an isolated drug effect separated from all other care.

The primary endpoint was assessed from the first dose of study drug until the end of colonoscopy. The registry describes the primary analysis population as all randomized patients, analyzed as randomized. Posted arm counts for this outcome were 32 for remimazolam, 16 for placebo, and 31 for midazolam. These endpoint counts should be read alongside the separate safety denominators, which differ for some arms. The reason for those differences is not reported in the registry record.

The brief summary describes the study as prospective, double-blind, randomized, placebo and active controlled, and multi-center. Further information about the sites, randomization procedure, allocation concealment, treatment adherence, or sample-size justification is not reported in the registry record. The design supports comparison of the randomized groups for the stated endpoint, but the details available do not establish how every operational feature was implemented.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All patients who were randomised, and analysed as randomised.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Baseline Analysis Population is the Safety Population

6. Primary Endpoint

The registry lists the primary outcome as Success Rates of the Procedure, measured over From first dose of study drug until the end of colonoscopy.

The primary endpoint was success of the colonoscopy procedure, reported as a count of participants. It was assessed from the first dose of study drug until the end of colonoscopy. A participant counted as a success only if the colonoscopy was completed, rescue sedative medication was not required, and the permitted study-medication dosing limit was not exceeded within the specified time window.

For remimazolam and placebo, the definition excluded success if more than 5 doses of study medication were needed within any 15 minute window. For midazolam, the corresponding limit was 3 doses within any 12 minute window. The distinction matters: the endpoint used regimen-specific dose limits, so the same wording cannot be treated as an identical dosing threshold across all arms.

This combined endpoint captures completion and the need for additional sedation or repeated study-drug dosing. Such a definition can be useful when the research question concerns whether a procedure was completed under a specified sedation strategy, rather than a single physiological measurement. At the same time, a combined outcome does not show which component was chiefly responsible for a success or failure. The posted results do not break out the separate contributions of colonoscopy completion, rescue medication, and dose limits.

The registry identifies the primary population as all randomized patients analyzed as randomized. The outcome therefore concerns the recorded success classification in that analysis population; it is not a direct measure of every aspect of sedation quality, recovery, or patient experience. Time to start of procedure and time to fully alert were listed as secondary outcomes, but their numerical results are not reported in the registry record.

7. Results Posted in the Registry

• Remimazolam: 84.4% (27/32) versus 0.0% (0/16) on control; risk difference 84.4 percentage points (95% CI 71.8 to 97.0); unadjusted two-proportion z-test p = <0.001.
• Midazolam: 12.9% (4/31) versus 0.0% (0/16) on control; risk difference 12.9 percentage points (95% CI 1.1 to 24.7); unadjusted two-proportion z-test p = 0.133.

8. Statistical Interpretation

9. Statistical Methods Explained

What does the risk difference describe?

For a binary outcome, each participant is classified as having or not having the event of interest. Here, the event is meeting the definition of procedure success. A risk difference expresses the difference between the proportions with the event in two groups. It is an absolute contrast, rather than a relative comparison. The reported values are 0.844 for remimazolam versus placebo and 0.129 for midazolam versus placebo. No further conversion is needed to interpret those posted estimates.

Because the endpoint is binary, the arm counts provide the underlying observed pattern: 27 of 32 successes with remimazolam, 0 of 16 with placebo, and 4 of 31 with midazolam. Counts are important context for any estimate. In particular, a zero count in the placebo arm affects how much information the data provide about that group’s underlying event probability. It should not be read as proof that the probability is exactly zero.

What does a confidence interval add?

A confidence interval describes a range of values compatible with the observed data under the statistical procedure used to construct it. In general, it conveys uncertainty around an estimate; a narrower interval indicates greater precision than a wider interval, all else being equal. It is not a range containing a fixed percentage of individual outcomes, and it is not a direct probability statement about where the true effect lies after observing the data.

The registry reports intervals from 0.718 to 0.970 for the remimazolam risk difference and from 0.011 to 0.247 for the midazolam risk difference. The remimazolam interval lies well above zero. The midazolam interval also lies above zero, while its accompanying unadjusted p-value is 0.133. The registry does not report the interval construction method or enough analysis detail to explain this difference in statistical signals. Both quantities should therefore be presented without assuming they arose from a single, internally matched procedure.

How should p-values be read?

In general, a p-value measures how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the test assumptions held. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The posted unadjusted p-value for remimazolam versus placebo is <0.001; for midazolam versus placebo it is 0.133. These values are unadjusted, and the registry record does not report multiplicity adjustment or the testing method.

A p-value should be read alongside the effect estimate, interval, observed counts, and design. It should not be used alone to describe precision or importance. In particular, interpreting a result solely through a threshold can obscure the uncertainty associated with limited group counts and the endpoint’s combined definition.

What can be said about planning illustrations?

The planning illustrations are based on the observed effect, rather than the trial’s own design justification. Their stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set as a stated fraction of the observed effect. They are illustrations of planning scenarios, not observed power and not evidence that the trial was designed with those assumptions.

For non-time-to-event outcomes, the planning quantities are expressed as participants per arm for 80% power or other stated power levels. The registry record does not report the trial’s sample-size justification, so these illustrations should not be treated as the original design calculation. A planning calculation also does not change the observed endpoint counts or provide additional trial evidence.

Why does over-dispersion matter in general?

Over-dispersion is relevant to some count-data models when the observed variability exceeds what a simpler model assumes. It can affect standard errors and confidence intervals if a model relies on an inadequate variance assumption. This trial’s primary outcome is binary and reported as participant counts, and no over-dispersion parameter is reported in the registry record. Therefore, over-dispersion is not a reported feature of the primary analysis and should not be invoked to explain these results.

More generally, analysis methods are part of the evidence because the method determines how uncertainty and hypothesis tests are calculated. The registry record reports the risk differences, intervals, and unadjusted p-values, but does not report the statistical procedures behind them. No adjusted estimates, model-based covariate results, or analysis specifications are reported in the registry record. The results can be described as posted, but the absent details limit independent assessment of the calculations.

10. Confidence Intervals and Precision

The remimazolam versus placebo risk difference was 0.844, with a confidence interval from 0.718 to 0.970. This interval is above zero throughout and is comparatively concentrated around the reported estimate. It conveys uncertainty in the contrast, not certainty about what would happen in another trial or setting. The observed endpoint counts were 27 of 32 for remimazolam and 0 of 16 for placebo.

The midazolam versus placebo risk difference was 0.129, with a confidence interval from 0.011 to 0.247. This interval also lies above zero, but its p-value was 0.133. The registry does not report how the confidence interval and p-value were calculated, so their differing signals cannot be interpreted by assuming they use matching methods or assumptions.

In general, confidence intervals communicate the range of estimates compatible with the data under a specified method. Their width reflects statistical precision, which depends on factors including the amount of information and variability. They do not show the range of individual participant outcomes, and they do not eliminate uncertainty about bias, endpoint interpretation, or generalizability.

The arm counts are limited, particularly for the placebo group, and the observed zero successes there make the estimate sensitive to the sparse outcome pattern. The registry record does not report interval methods, missing-outcome handling, or details that would allow further assessment of precision. The safety denominators also differ from the primary-outcome denominators in some arms, so the safety counts should not be substituted for the endpoint counts.

11. Multiplicity, Missing Data and Analysis Populations

The record lists three outcome measures and two posted secondary outcomes: time to start of procedure and time to fully alert. Their numerical results are not reported in the registry record. The primary endpoint has posted results for the three arms, along with two unadjusted pairwise comparisons against placebo.

When multiple outcomes or comparisons are examined, the chance of at least one apparently notable result can increase. Statistical procedures can address this issue by controlling the family of tests, but no multiplicity adjustment or testing hierarchy is reported in the registry record. The reported p-values should therefore be read as unadjusted, not as multiplicity-controlled evidence.

The registry record does not report how missing primary-outcome observations were handled, whether any participants lacked endpoint data, or whether sensitivity analyses were conducted. The stated primary population is all patients randomized and analyzed as randomized, but the record does not provide further detail about implementation of that population or the handling of departures from it. The reason the safety denominators differ from some primary-outcome denominators is not reported in the registry record.

The record also does not report interim analyses, a detailed statistical analysis plan, the test used for the p-values, or the method used to construct the confidence intervals. These omissions limit assessment of whether the analyses followed a prespecified approach and how robust the results are to alternative assumptions. They do not change the posted counts or estimates, but they constrain the conclusions that can be drawn from them.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anaemia (3.3%).

The serious adverse event summary reports 0 affected participants among 31 at risk in the remimazolam group, 0 among 16 in the placebo group, and 1 among 30 in the midazolam group. No deaths were reported in any of these groups. Anaemia is listed among the top serious adverse event terms at 3.3%. The record does not give further detail about the event’s timing, clinical course, or attribution.

These are counts of affected participants, not a measure of event severity beyond the serious-event classification. A group with no recorded serious adverse events has not thereby been shown to have no risk; a small study can observe no events even when an underlying risk exists. The safety denominators differ from the primary-outcome arm counts for remimazolam and midazolam, and the reason is not reported in the registry record.

Other adverse events affected 28 of 31 participants in the remimazolam group, 13 of 16 in the placebo group, and 26 of 30 in the midazolam group. These figures are separate from serious adverse events and should not be combined with them. The registry record does not provide a complete event-level account in these summary figures, so they do not describe event duration, recurrence, or comparative causality.

13. What the Result Does, and Does Not, Mean

The posted results show that the observed procedure-success counts differed between the remimazolam and placebo groups: 27 of 32 participants met the endpoint with remimazolam, compared with 0 of 16 with placebo. The reported risk difference was 0.844, with a confidence interval from 0.718 to 0.970 and an unadjusted p-value of <0.001. For midazolam, 4 of 31 participants met the endpoint; the reported risk difference versus placebo was 0.129, with a confidence interval from 0.011 to 0.247 and an unadjusted p-value of 0.133.

These estimates describe the trial’s recorded endpoint under its treatment regimens and study conditions. They do not prove that the underlying probability of success is zero with placebo, nor do they establish what results would be observed in a different patient population or procedural setting. The endpoint combines completion, rescue sedation, and study-medication dosing requirements, so the results cannot isolate the contribution of any one component.

The findings also do not establish broader comparative safety. The serious adverse event counts were small, and the other adverse event counts are summary figures rather than a detailed account of event types and courses. The registry record does not report secondary-outcome values, missing-data procedures, adjusted analyses, or a full statistical analysis plan.

In general, randomized comparisons can help estimate differences between assigned groups, but interpretation depends on outcome definitions, trial conduct, analysis methods, and precision. The posted data should therefore be read as evidence about this particular trial and its stated endpoint, not as a standalone conclusion about all outcomes or all patients undergoing colonoscopy.

14. Why This Trial Matters Statistically

This trial illustrates why endpoint definitions matter. Procedure success was not simply colonoscopy completion: it also required no rescue sedative medication and compliance with study-drug dose limits. A reader interpreting the group counts needs to keep all of these conditions in view. The definition also used different dose limits for midazolam than for remimazolam and placebo, which means that the endpoint’s medication component was regimen-specific.

The comparison also illustrates the value of reporting absolute contrasts alongside counts. The risk difference describes the observed separation in the proportions meeting the binary endpoint, while the counts show the size and pattern of the data behind that estimate. The placebo group had no recorded successes, so the estimated contrasts and their uncertainty should be interpreted with attention to the sparse pattern rather than as exact descriptions of underlying event probabilities.

Finally, the record shows why statistical conclusions depend on transparent methods. It reports estimates, confidence intervals, and unadjusted p-values, but does not report the procedures used to calculate them or the approach to multiplicity and missing data. The midazolam interval and p-value also give different signals under common reference points, making the absence of method details especially relevant. These issues do not erase the posted results; they clarify what can and cannot be assessed from the registry record.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record gives limited detail about how the study was conducted and analyzed. It does not report the randomization sequence, allocation concealment, masking procedures by role, statistical analysis plan, sample-size justification, or methods for confidence intervals and p-values. The brief summary describes the midazolam arm as open-label, which is relevant when considering possible differences in care or outcome assessment across arms.

The primary outcome is a composite procedural definition. The posted results do not separate colonoscopy completion from rescue medication use or study-medication dosing. The dose limits also differ for midazolam compared with the remimazolam and placebo arms, so the endpoint incorporates different regimen-specific rules.

The record lists the secondary outcomes but does not report their numerical results. It also does not report missing-data handling, interim analyses, multiplicity adjustments, or sensitivity analyses. The reason that safety denominators differ from primary-outcome denominators in some arms is not reported in the registry record. The safety summaries do not provide full event-level details, timing, or causal attribution.

The observed counts are limited, and the placebo group had no primary-outcome successes. This makes careful interpretation of uncertainty important. The results describe the trial’s recorded population and setting; the registry record does not provide enough detail to determine how broadly they apply beyond that context.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of Remimazolam in ASA III and IV Patients Undergoing Colonoscopy — NCT02532647.
• Registry record last updated 2020-09-30; status last verified 2020-09.
• Results first posted 2019-01-23.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT02532647 is a completed phase 3 randomized parallel-group study of remimazolam, placebo, and midazolam in patients with ASA III or IV status undergoing colonoscopy. The registry describes the remimazolam-placebo comparison as double-blind and the midazolam arm as open-label. The primary endpoint was procedure success, defined using colonoscopy completion, rescue sedative use, and study-medication dose limits.

Success was recorded for 27 of 32 participants with remimazolam, 0 of 16 with placebo, and 4 of 31 with midazolam. The reported remimazolam-placebo risk difference was 0.844, with a confidence interval from 0.718 to 0.970 and p <0.001. The midazolam-placebo risk difference was 0.129, with a confidence interval from 0.011 to 0.247 and p = 0.133. Serious adverse events affected 0 of 31, 0 of 16, and 1 of 30 participants, respectively. Further analysis details and numerical secondary-outcome results are not reported in the registry record.